(a) Field of the Invention
This invention relates to 5-[(aromatic-heteryl)carbonyl]-6-methyl-2(1H)-pyridinones, their preparation, and their use as cardiotonic agents and intermediates.
(b) Information Disclosure Statement
Lesher and Singh in U.S. Pat. No. 4,415,580, issued Nov. 15, 1983, show as cardiotonic agents 5-(lower-alkyl)-1,6-naphthyridin-2(1H)-ones (I) and their preparation by reacting a 5-(lower-alkanoyl)-6-methyl-2(1H)-pyridinone with di-(lower-alkyl)formamide di-(lower-alkyl)acetal to produce 5-(lower-alkanoyl)-6-[2-(di-lower-alkylamino)ethenyl]-2(1H)-pyridinone (II) and reacting II with formamidine or ammonia or salt thereof to produce I.
Lesher and Singh in U.S. Pat. No. 4,412,077, issued Oct. 25, 1983, show as cardiotonic agents 5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinones (I) and their preparation by reacting 2-(lower-alkanoyl)-1-(lower-alkyl)-ethenamine (II) with a lower-alkyl 2-propynoate.
Copending U.S. patent application Ser. No. 630,810, filed July 13, 1984, now U.S. Pat. No. 4,560,691 issued Dec. 24, 1985, discloses and claims 5-(benzoyl and selected substituted-benzoyl)-6-methyl-2(1H)-pyridinones, their preparation, their use as intermediates for preparing selected 5-(phenyl)-1,6-naphthyridin-2(1H)-ones (cardiotonic agents) and the use of 5-(benzoyl or hydroxybenzoyl)-6-methyl-2(1H)-pyridinone as a cardiotonic agent.
Merrell Dow Pharmaceuticals Inc. (Inventors: Winton D. Jones, Richard A Schnettler and Richard C. Page) European Patent Application No. 124090, published Nov. 7, 1984, filed Apr. 26, 1984 and having a U.S. priority of Apr. 29, 1983 (U.S. application Ser. No. 490,081), now U.S. Pat. No. 4,568,751, has the following generic teaching:
"More specifically, this invention relates to pharmaceutically active 5-acyl-2-(1H)-pyridinones of the formula I ##STR1## and the pharmaceutically acceptable salts thereof, wherein R.sub.3 is H, --C.dbd.N, NH.sub.2, CONH.sub.2 and COOR with
R being hydrogen or lower alkyl, PA1 R.sub.4 is hydrogen or lower alkyl, PA1 R.sub.5 is phenyl, X-substituted phenyl, pyridyl, thienyl, furyl, pyrrolyl and OR wherein R is hydroxy or lower alkoxy, and X is lower alkyl, lower alkoxy, lower alkyl thio, halogen, nitro, lower alkanoyl, alkoxy carbonyl, carboxy, cyano, NH.sub.2, CONH.sub.2, amidino, imidazol-2-yl, and CF.sub.3, and PA1 R.sub.6 is hydrogen, methyl, ethyl or R.sub.5. These compounds are useful as cardiotonics in the treatment of cardiac failure and other conditions requiring strengthening of heart action with a cardiotonic agent." Compounds specifically disclosed are all nicotinonitriles, that is, compounds of formula I where R.sub.3 is cyano. Included among these nicotinonitriles are: 5-(R.sub.5 CO)-6-ethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitriles where R.sub.5 is 4-pyridinyl, 2-thienyl and 3-furanyl, "and the 6-methyl homologs thereof." Illustrative of the preparation of these compounds is the reaction of 1-benzoylacetone with dimethylformamide dimethyl acetal to produce 2-[(dimethylamino)methylene]-1-phenyl-1,3-butanedione (Ex. 1) and reaction of the dione with cyanoacetamide in the presence of sodium hydride in tetrahydrofuran to produce 5-acetyl-1,2-dihydro-2-oxo-6-phenyl-3-pyridinecarbonitrile. Specifically named intermediate 2-[(dimethylamino)methylene]-1-R.sub.5 -1,3-butanediones include those where R.sub.5 is 4-pyridinyl, 2-thienyl and 3-furanyl.